Protein tyrosine kinases are a class of enzymes that catalytically transfers phosphate groups from ATPs to tyrosine residues located at a protein substrate, which play a role in normal cell growth. A variety of growth factor receptor proteins act via tyrosine kinases, affect signaling through this process, and in turn regulate cell growth, e.g., FGFR (Fibroblast growth factor receptor), VEGFR (Vascular endothelial growth factor receptor) and PDGFR (Platelet-derived growth factor receptor). However, under certain conditions, these receptors are either mutated or overexpressed, and become abnormal, thereby causing uncontrolled proliferation of cells, resulting in tumor growth, and finally leading to well-known diseases cancers. Growth factor receptor protein tyrosine kinase inhibitors inhibit the phosphorylation process, and act to treat cancers or other diseases characterized by uncontrolled or abnormal cell growth.
Uncontrolled angiogenesis is a mark of cancers. In 1971, Dr. Judah Folkman proposed that the tumor growth depended on angiogenesis (see, Folkman, New England Journal of Medicine, 285: 1182-86 (1971). In accordance with Dr. Folkman, tumors can merely grow to a certain size in absence of additional blood vessels to nourish the tumors. In its simplest statement, the proposals recites that once a tumor “lives (survives)”, each increase in tumor cell population must be made by an increase in new capillaries that converge in the tumor. The “living (survival)” of tumor as currently understood refers to the vascular prophase of tumor growth, in which tumor cell population occupying cubic millimeters in volume and containing no more than millions of cells can survive on the existing host microvasculature.
It has indicated that tumors can be treated by inhibiting the angiogenesis, instead of the proliferation of tumor cells themselves. Angiogenesis has been associated with a large number of different types of cancers, including solid tumors and blood-borne tumors. The angiogenesis-associated solid tumors comprise, but are not limited to: rhabdosarcoma, retinoblastoma, Ewing's sarcoma, neuroblastoma, and osteosarcoma. Angiogenesis is associated with breast, prostate, lung, and colon cancers. Angiogenesis is also associated with blood-borne tumors, including any one of leukemia, lymphoma, multiple myeloma, and various acute or chronic bone marrow neoplasms which involve unrestricted proliferation of white blood cells, and are generally accompanied with anemia, decreased blood coagulation, as well as enlargement of lymph nodes, liver, and spleen. It is also believed that angiogenesis plays a role in bone marrow disorders, which cause leukemia, lymphoma and multiple myeloma.
Angiogenesis plays a primary role in cancer metastasis, and if the vasogenic activities can be inhibited or eliminated, tumors would not grow even though they are present. Under the state of disease, the prevention of angiogenesis can reduce damages caused by invasion of new microvasculature. Therapies for controlling vasogenic processes may lead to the elimination or alleviation of these diseases.
Of those, the study of inhibiting angiogenesis by FGFR (Fibroblast growth factor receptor), VEGFR (Vascular endothelial growth factor receptor) and PDGFR (Platelet-derived growth factor receptor) inhibitors tends to be mature.